1 Department of Neurology, National Neurological AIDS Bank, David Geffen School of Medicine at the University of California, Los Angeles, CA, USA

2 Department of Human Genetics, David Geffen School of Medicine at the University of California, Los Angeles, CA, USA

3 Department of Medicine (Division of Infectious Disease & International Medicine) and Department of Psychiatry & Behavioral Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

Abstract

Background

Human Immunodeficiency Virus-1 (HIV) infection frequently results in neurocognitive
impairment. While the cause remains unclear, recent gene expression studies have identified
genes whose transcription is dysregulated in individuals with HIV-association neurocognitive
disorder (HAND). However, the methods for interpretation of such data have lagged
behind the technical advances allowing the decoding genetic material. Here, we employ
systems biology methods novel to the field of NeuroAIDS to further interrogate extant
transcriptome data derived from brains of HIV + patients in order to further elucidate
the neuropathogenesis of HAND. Additionally, we compare these data to those derived
from brains of individuals with Alzheimer’s disease (AD) in order to identify common
pathways of neuropathogenesis.

Methods

In Study 1, using data from three brain regions in 6 HIV-seronegative and 15 HIV + cases,
we first employed weighted gene co-expression network analysis (WGCNA) to further
explore transcriptome networks specific to HAND with HIV-encephalitis (HIVE) and HAND
without HIVE. We then used a symptomatic approach, employing standard expression analysis
and WGCNA to identify networks associated with neurocognitive impairment (NCI), regardless
of HIVE or HAND diagnosis. Finally, we examined the association between the CNS penetration
effectiveness (CPE) of antiretroviral regimens and brain transcriptome. In Study 2,
we identified common gene networks associated with NCI in both HIV and AD by correlating
gene expression with pre-mortem neurocognitive functioning.

Conclusions

While under-powered, this study identified possible biologically-relevant networks
correlated with NCI in HIV, and common networks shared with AD, opening new avenues
for inquiry in the investigation of HAND neuropathogenesis. These results suggest
that further interrogation of existing transcriptome data using systems biology methods
can yield important information.